Penicillins substituted with heterocyclic groups

ABSTRACT

A penicillin of the formula:   WHEREIN A is a substituted or unsubstituted condensed aromatic carbocyclic or heterocyclic ring, R is hydrogen or lower alkyl, X is oxygen or sulfur, Y is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl and Z is phenyl or thienyl which can be produced by reacting 6-aminopenicillanic acid or its ester with a carboxylic acid of the formula:   WHEREIN A, R, X, Y and Z are each as defined above or its reactive derivative. The said penicillin and its non-toxic salts have a broad antimicrobial spectrum against various gram-positive and gram-negative bacteria, and they exhibit characteristically a strong antimicrobial activity against Pseudomonas.

United States Patent [1 1 Tobiki et al.

14 1 Feb. 4, 1975 [73] Assignee: Sumitomo Chemical Company,

Limited, Osaka, Japan [22] Filed: Sept. 26, 1972 [2!] Appl. No.: 292,325

Related US. Application Data [63] Continuation-in-part of Ser. No.213,745, Dec, 29,

1971, abandoned.

[52] US. Cl 260/239.1, 424/271, 260/287,

260/289, 260/283 S, 260/296 N [S l] Int. Cl C07d 99/16 [58] Field ofSearch 260/239.l

[56] References Cited UNITED STATES PATENTS 3,433,784 3/[969 Long et al260/239] Primary Examiner-Donald G. Daus Assistant Examiner-Mary C.Vaughn Attorney, Agent, or Firm-Stewart and Kolasch, Ltd,

[ ABSTRACT A penicillin of the formula:

cs 0NH-CH-CONH l CH3 2 N o coon wherein A is a substituted orunsubstituted condensed aromatic carbocyclic or heterocyclic ring, R ishydro gen or lower alkyl, X is oxygen or sulfur, Y is hydro gen, loweralkyl, lower alkanoyl or lower alkoxycarbonyl and Z is phenyl or thienylwhich can be produced by reacting o-aminopenicillanic acid or its esterwith a carboxylic acid of the formula:

CONH-fH-COOH wherein A, R, X, Y and Z are each as defined above or itsreactive derivative. The said penicillin and its non-toxic salts have abroad antimicrobial spectrum against various gram-positive andgram-negative bacteria, and they exhibit characteristically a strongantimicrobial activity against Pseudomonas.

12 Claims, No Drawings PENICILLINS SUBSTITUTED WITH HETEROCYCLIC GROUPSThis is a continuation-in-part application of Ser. No. 2l3,745, filedDec. 29, l97l, now abandoned.

This invention relates to penicillins and their produc tion. Moreparticularly. it relates to novel derivatives of6-(a-aminophenylacetamidoJ-penicillanic acid and o-(a-aminothienylacetamido)-penicillanic acid and their production.

As is well known, 6-(a-aminophenylacetamidolpenicillanic acid (i.e.,ampicillin) inhibits the growth of various gram-positive andgram-negative bacteria but does not exert any appreciable antimicrobialactivity against Pseudomonas. In Japanese Pat. No. 20986/69. there aredescribed some N-acyl derivatives of said ampicillin as showing aminimal inhibitory concentration of 125 to 250 ug/ml against Pseudomonaspyocinea A or R 59, when determined by the standard test method. Theanti-Pseudomonas activity of the compounds as described in the workingexamples is, however, not so high and the antimicrobial activity againstother grampositive and gram-negative bacteria is considerably low. Thus,it may be said that the N-acyl derivatives of ampicillin are lessvaluable from the practical viewpoint.

As the result of the study seeking novel penicillins which have a broadantimicrobial spectrum and are highly active against gram-positive andgram-negative bacteria including Pseudumunas, it has been found that,among various compounds, the penicillins of the following formulacharacteristically exhibit a noticeable antimicrobial activity againstPseudomunas:

wherein A is a substituted or unsubstituted condensed aromaticcarbocyclic or heterocyclic ring, R is hydrogen or lower alkyl, X isoxygen or sulfur, Y is hydrogen, lower alkyl, lower alkanoyl or loweralkoxycarbonyl and Z is phenyl or thienyl. They exhibit also a highantimicrobial activity abainst other gram-positive and gram-negativebacteria. This invention is based on the above finding.

Accordingly, it is a basic object of the present invention to providethe penicillins [l] and their non-toxic salts. Another object of thisinvention is to provide a process for preparing the penicillins ]l] andtheir nontoxic salts. A further object of the invention is to providethe antimicrobial agents useful for controlling various gram-positiveand gram-negative bacteria including Pseudomrmus. These and otherobjects of the invention will be apparent to those skilled in the artfrom the foregoing and subsequent descriptions.

In the above formula ll], the condensed aromatic carbocyclic andheterocyclic ring represented by the symbol A may be benzene,naphthalene or a sixmembered heteroaromatic ring containing nitrogen asthe hetero atom, etc. Examples ofthe substituent which may be present onsuch ring are lower alkyl (e.g., methyl, ethyl. propyl, isopropyl,butyl), lower alltoxy lug, methoxy, ethoxy, propoxy. huthoxyl, loweralk- 2 oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl), hydroxyl, halogen (e.g., chlorine. bromine, iodine,fluorine), halo(lower)alkyl (e.g.. chloromethyl, trifluoromethyl),nitro, lower alkylsulfonyl (cg, methylsulfonyl), mercapto, loweralkylthio (e.g., methylthio, ethylthio, propylthio) lower alkylenedioxy(cg, methylenedioxy. cthylenedioxy lower alkylene (e.g., trimethylene,tetramethylene), amino. lower alkylamino (e.g., methylamino. ethylamino,propylamino), ditlowerlalkylamino (e.g.. dimethylamino. diethylamino.methylethylamino). etc. When the substituent is amino or loweralkylamino, it may be present in any protected form conventionallyemployed in peptide syntheses. e.g., bearing a protecting group (e.g.,acetyl, carbobenzoxy. trichloroethoxycarbonyl. o-nitrophenylsulfenyl) ortaking a protected structure (e.g., enamine). The number of thesubstituent is usually from 1 to 3, if present.

The term "lower is intended to mean the group having up to 8 carbonatoms throughout the specification. Particularly preferred are thosehaving 1 to 4 carbon atoms for the alkyl moiety and the alkylene moiety.

The non-toxic salts of the penicillins [l] are, for instance, the alkalimetal salts (e.g., sodium, potassium salts), the alkaline earth metalsalts (e.g., calcium, harium, magnesium salts], the substituted andunsubstituted ammonium salts, the arginine salt, etc. All these areconventional salts in the related art field.

According to the present invention, the penicillin [I] can be producedby reacting 6-aminopenicillanic acid or its ester with a carboxylic acidof the formula:

CONH-CH-COOH wherein A, R, X, Y and Z are each as defined above or itsreactive derivative.

One of the starting materials is o-aminopenicillanic acid or its ester.The ester is required to recover carboxyl by hydrogenation, hydrolysisor any other appropriate chemical treatment after accomplishment of theamidation, and specific examples thereof include the trialkylsilylester, trichloroethyl ester, lower alkanoyloxymethyl ester, phenacylester, etc. All these esters are conventional in the related art field.

The other starting material is the carboxylic acid [II] or its reactivederivative. Examples of the reactive derivative of the carboxylic acid[ll] are the acid halide, acid azide, acid anhydride, mixed acidanhydride, active ester (e.g., p-nitrophenyl ester, N-hydroxysuccinimide ester], active thioester, active thioacid anhyclride,active amide (cg, imidazole amide. triazole amide), etc.

The carboxylic acid [ll] or its ester may be produced. for instance, byreacting an amino acid of the formula:

[III] Z wherein Z is as defined above or its ester with a carhoxylicacid of the formula;

wherein A. R. X and Y are each as defined above or its reactivederivative in an appropriate solvent (e.g.. methanol. ethanol.dichloromethane. chloroform. dioxane. acetone. dimethylformamide) in thepresence of a basic substance (e.g., pyridine. trimethylaminel at atemperature from about 50 to 80C. if necessary. followed by hydrolysis.

The reaction between fi-aminopenicillanic acid or its ester and thecarboxylic acid [ll] or its reactive derivative is usually effected inan inert solvent such as a polar solvent (cg, dichloromethane,chloroform, acetone. tetrahydrofuran. dioxane, acetonitrile,dimethylformamide) or a non-polar solvent leg. benzene, tolueneJ. ortheir mixtures. The inert solvent may sometimes include water. Thereaction temperature is normally from about U to 80 C. and the executionunder cooling with ice is preferred.

in case that the carboxylic acid [ll] wherein Y is hydrogen is subjectedto amidation in the reacted form with an alkanoyl halide orall-toxycarbonyl halide, one molar amount of the carboxylic acid isfirst reacted with at least two molar amounts of the acylating agent inthe presence ofat least two molar amounts ofa basic substance and thenthe resulting product is reacted with b-aminopenicillanic acid or itsester to give the penicillin [I] wherein Y is lower alltanoyl or loweralkoxycarbonyl. Hydrolysis ofthe latter with an organic or inorganicbasic substance. particularly with an aqueous solution ofalkali metalcarbonate (cg. sodium carbonate. potassium carbonate). affords thecorresponding penicillin [I] wherein Y is hydrogen.

The penicillin [I] can be also produced by reactingb-lu-amino-substituted-acetamidoJ-penicillanic acid of the formula:

a N H CONH s CH3 2 I OJ: Eori cooH wherein Z is as defined above or itsester with the carboxylic acid [W] or its reactive derivative.

One of the starting materials is 6-01-aminosubstituted-acetamido)-pencillanic acid [V] or its ester. Theester is required to recover carboxyl by hydrogenation. hydrolysis orany other appropriate chemical treatment after accomplishment of theamidation. specific examples thereof include the trialkylsilyl ester.trichloroethyl ester. lower alkanoyloxymethyl ester. phenacyl ester.etc. All these esters are conventional in the related art field.

The other starting material is the carhoxylic acid [N] or its reactivederivative Examples ofthc reactive derivative of the carboxylic acid[IV] are the acid halide. acid azidc, acid anhydride. mixed acidanhydride. active ester (e.g.. p-nitrophenyl ester. N hydroxysuccinimideester), active thioester. active thioacid anhydride. active amide leg.imidazole amide. triazole amide). etc.

The reaction between the b-( a-amino-substituted acetamidoi-penicillanicacid [V] or its ester and the carboxylic acid [IV] or its reactivederivative is usually effected in an inert solvent as mentioned above.The reaction temperature is ordinarily from about -5U to C. and theperformance under cooling with ice is favorable.

In case that the carboxylic acid [IV] wherein Y is h drogen is subjectedto amidation in the reacted form with an alkanoyl halide oralkoxycarhonyl halide. one molar amount of the carhoxylic acid is firstreacted with at least two molar amounts of the acylating agent in thepresence of at least two molar amounts of a basic substance and then theresulting product is reacted with the b-a-amino-substituted-acetamidopenicillanic acid [V] or its ester to give the penicillin [l] wherein Yis lower alkanoyl or lower alkoxycarbonyl. Hydrolysis of the latter withan organic or inorganic basic substance, particularly with an aqueoussolution of alkali metal carbonate (e.g.. sodium carbonate. potassiumcarbonate). affords the corresponding penicillin [11 wherein Y ishydrogen.

In case that the carboxylic acid [IV] wherein Y is hydrogen is subjectedto amidation in the reacted form with phosgene. thionyl chloride,phosphorus trichloridc or the like. one molar amount of the carboxylicacid is first reacted with one molar amount of the reagent in thepresence of at least two molar amounts of a basic substance and then theresulting product is reacted with the6-(a-amino-substituted-acetamidojpenicillanic acid [V] or its ester togive the penicillin [I] wherein Y is hydrogen.

Further. the penicillin [I] wherein the ring A is sub stituted withamino or lower alkylamino can be pro duced from the correspondingcompound bearing a group convertible to amino or lower alkylamino on thering A. Examples of the group convertible to amino or lower amino arenitro. protected amino. protected lower alkylamino. etc. The protectinggroup in case of protected amino and protected lower alkylamino may bethose as are conventionally employed in peptide synthesis. When thesubstituent is nitro. it can be converted into amino by a per seconventional hydrogenation procedure in the presence or absence of anyappropriate catalyst. When the substituent is protected amino orprotected lower alkylamino. there is usually employed hydrogenation orhydrolysis. In any case. the adoption of a mild reaction condition isnecessary for avoiding the opening of the B-laetam ring in the penicil'lin nucleus.

The thus produced penicillin [i] may be converted into any non-toxicsalt by a per se conventional procedure.

As stated above. the penicillins [I] and their nontoxic salts accordingto this invention are useful as antimicro bial agents against variousgram-positive and gramnegative bacteria including Pseudomunur and may heused in the same manner as applied to conventional an timicrobial agentssuch as ampicillin.

Practical and presently preferred embodiments of the present inventionare illustratively shown in the following Examples.

EXAMPLE l Preparation of D-(-)- 4ethoxycarbonyloxyquinoline-3-carbonamido benzylpenicillin:

1. D-( )-(r-( 4-Hydroxyquinoline-3-carbonamido phenylacetic acid.

Dichloromethane (50 ml) is added to 4- hydroxyquinoline-3-carboxylicacid (2.5 g). and 29.6 percent phosgene-dichloromcthane (4.4 g) is addedthereto under cooling. After the dropwise addition of triethylamine (2.7g) at -20 to 25C. D-(-)-aphenylglycine ethyl ester hydrochloride (2.86g) and triethylamine (1.4 g) are added to the resulting mixture.Stirring is continued at l5 to 20C for 1 hour. The reaction mixture iswashed with water. a solution of sodium hydroxide (lg) in water (20 ml)is added thereto and stirring is effected at 40C for 1 hour. The waterlayer is adjusted to pH 1 with hydrochloric acid to precipitate crudecrystals. Recrystallization of the crude crystals from dioxane affordsD-(-)-a-(4- hydroxyquinoline-3-earbonamido)-phenylacetic acid (1.1 g).M.P. 195C.

2. D-(-)-a-(4-Ethoxycarbonyloxyquinoline-3-carbon carbonamidoJ-benzylpenicillin:

The phenylacetic acid (1 g) as obtained in l) is admixed withtriethylamine (0.63 g) and dichloromethane (30 ml), and ethylchlorocarbonate (0.70 g) is added thereto at C. Stirring is continued atthe same temperature as above for 30 minutes. 6- Aminopenicillanic acidtriethylamine salt (0.985 g) is added to the resulting mixture at l0C,and stirring is continued at the same temperature as above for 3 hours.A dilute aqueous solution of sodium carbonate is added to the reactionmixture, and the water layer is separated and adjusted to pH 2.0 with lN hydrochloric acid. The resulting solution is extracted three timeswith ethyl acetate (50 ml), and the extract is washed with water, driedover anhydrous magnesium sulfate and concentrated at 25C under reducedpressure. The residue is crystallized from ether to give D-(-)-a-(4-ethoxycarbonyloxyquinoline-3-carbonamidobenzylpenicillin (1.3 g). M.P.l56.5 to l58.5C (decomp).

EXAMPLE 2 Preparation of D-()-a-(4-ethoxycarbonyloxyquinoline-3-carbonamido)- benzylpenicillin:

To a mixture of 4-hydroxyquinoline-3-carboxylic acid 1.88 g), dioxane(50 ml), acetone 10 ml) and triethylamine (2.02 g). there is dropwiseadded ethyl chlorocarbonate (2.16 g) while cooling. After stirring for30 minutes, D-(-)-a-aminobenzylpenicillin triethylamine salt (4.50 g) isadded to the resulting mixture, and stirring is further continued for 1hour. Then, a dilute aqueous solution of sodium hydrogen carbonate isadded to the reaction mixture. and the resultant mix ture is shaken withethyl acetate. The water layer is separated and acidified to pH 2 withdilute hydrochloric acid. The precipitate is extracted with ethylacetate. The extract is washed with water. dried over anhydrousmagnesium sulfate and concentrated at 25C. The separated crystals arewashed with ether and dried on phosphorus pentoxide to give D-(-)-oz-(4-ethoxycarbonyloxyquinoline-3-carbonamido)- benzylpenicillin (4.70 g).Purity (determined by iodometry). 88.5 percent.

EXAMPLE 3 Preparation of D-( -)-a-( 4-hydroxyquirtoline-3- carbonamido)-benzylpenicillin:

D-(-)-a(4-ethoxycarhonyloxyquinolinc-3- carbonamido)-henzylpenicillin1.18 g) is dissolved in an aqueous solution of sodium carbonate whilecooling. and the resulting solution is stirred for l hour. Afteracidifying to pH 2 with dilute hydrochloric acid. the precipitate isextracted with ethyl acetate, and the extract is washed with water.dried over anhydrous magnesium sulfate and concentrated at 25C. Theseparated crystals are washed with ether and dried over phosphoruspentoxide to give D-( )-a-( 4-hydroxyquinoline-3-earbonamido)-benzylpenicillin (0.95 g). Purity(determined by iodometry), 90.3 percent.

EXAMPLE 4 Preparation of D-(-)-a-(7-methyl-4-hydroxy-l.8-naphthyridinc-3-carbonamido)-benzylpenicillin potassium salt:

To D-(-)-a-(7-methyl-4-hydroxy-l.8-naphthyridine-3-carbonamido)-phenylacetic acid (M.P. 275C (dec0mp.)) (2g) preparedfrom 7-methyl-4-hydroxy-l.8- naphthyridine-3-carboxylic acid (Mp 288C(de comp.)) in the same procedure as in Example l (1). dichloromethane(50 ml) and triethylamine (1.2 g) are added, and ethyl chlorocarbonate(1.35 g) is dropwise added thereto at 0 to 5C. After stirring for 30minutes. 6-aminopenicillanic acid triethylamine salt 1.9 g) is added tothe resulting mixture. and stirring is further continued at the sametemperature as above for 3 hours. The reaction mixture is shaken with adilute aqueous solution of sodium carbonate. The aqueous layer isseparated, adjusted to pH 2 with hydrochloric acid while cooling andextracted with ethyl acetate. The extract is washed with water and driedover anhydrous magnesium sulfate. Then. a 50 percent n-butanol solutionof potassium Z-ethylhexanoate is added thereto. The separated crystalsare collected by filtration and washed with ether to giveD-(-)-a-(7-methyl- 4-hydroxy-l.8-naphthyridine-3-carbonamido)-benzylpenicillin potassium salt (2 g). M.P. 222 to 224C (decomp). Purity(determined by iodometry), percent.

EXAMPLE 5 Preparation of D-( )-a-( 7-methyl-4- ethoxycarbonyloxy-l,8-naphthyridine-3- carbonamido)-benzylpenicillin:

To a mixture of 4-hydroxy-7-methyl-l,8- naphthyridine-3-carboxy1ic acid(0.41 g). dioxane (45 ml), acetone (10 ml) and triethylamine (0.41 g).ethyl chloroformate (0.44 g) is dropwise added while cooling. Afterstirring for 30 minutes, D-(-)-aaminobenzylpenicillin triethylamine salt(0.90 g) is added thereto, and the resultant mixture is stirred furtherfor 1 hour. The reaction mixture is admixed with a dilute aqueoussolution of sodium hydrogen carbonate and shaken with ethyl acetate. Thewater layer is adjusted to pH 2 with dilute hydrochloric acid, and theprecipitate is extracted with ethyl acetate. The extract is washed withwater. dried over anhydrous magnesium sulfate and concentrated at 25C.The separated crystals are washed with ether and dried over phosphoruspentoxide to give D-( )-a-( 7-methyl-4ethoxycarbonyloxyl,8-naphthyridine-3- carbonamidoJ-benzylpenicillin(0.85 g).

EXAMPLE 6 chloric acid and water, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The obtained crystals (1.05 g)of D-(-)-a (4- pivaloyloxyquinoline-3-carb0namido)-benzylpenieillin arepurified by dissolving into a small amount of ethyl acetate and addingether thereto so as to precipitate crystals. Purity (determined byiodometry), 89.5 percent.

EXAMPLE 7 Preparation of D-(-)-a-(2-methyl-6.7-methylenedioxy-4-hydroxyquinoline-3-carbonamido)- benzylpenicillinpotassium salt:

1. D-(-)-a-(Z-Methyl-6,7-methylenedioxy-4-hydroxyquinoline-3-carbonamido)-phenylacetic acid.

To a mixture of 2-methyl-6.7-methylenedioxy-4-hydroxyquinoline-3-carboxylie acid (M.P. 340C (decompJl (2 g).dichloromethane (60 ml) and triethylamine (L65 g), ethyl chlorocarbonateL8 g) is dropwise added thereto at l0C. After 30 minutes. D-(-)-a-phenylglycine ethyl ester hydrochloride (L? g) and triethylamine (0.85g) are added thereto at the same temperature as above and stirring iseffected for 4 hours. The reaction mixture is treated as in Example I(l) to give D-(-)-a-(2-methyl-6 7-methylenediox -4-hydroxyquinoline-3-carbonamido)-phenylacetic acid (1.5 g) as crystals.M.P. 250C (decomp).

2. D-(-)-a-(2-Methyl-6,7-methylenedioxy-4-hydroxyquinoline-J-carbonamido)-benzylpenicillin potassium salt.

To a mixture of D-(-)-a-(2-methyl-6.7-methylenedioxy-4hydroxyquinoline-3-carbonamido)- phenylacetic acic (lg). dichloromethane (30 ml) and triethylamine (0.53 g), pivaloylchloride (0.72 g) is added thereto at 0 to 3C. After stirring for 20minutes. (i-aminopenicillanic acid triethylamine salt (0.8 g) is added,and the resulting mixture is stirring at 0 to 5C. for 5 hours. Thereaction mixture is treated as in Example 4 to give D-( J-(Z-methyl-(uJmethylenedioxy-4-hydroxyquinoline-3-carbonamido)- bcnzylpenicillinpotassium salt (L2 g) as crystals. Purity (determined by iodometry), 82percent. Water content, 6.7 percent.

EXAMPLES 8 to 60 ln the same procedure as above, there are produced thefollowing penicillins [l]:

Eiam- Chemical structure lEurity p e d t: i a No by i m i zry) SC H 8CONH- H-CONHjiE 395 0 N o N COOH 0 N G o N COOH 0CH3 CH 10 c0NHcH'-CNH-f 80.6 x.

CH3 11 CHSS I coriH-cH NH;[:f CH3 80.8 v.

\ 0 N COOH 06113011 CONii-CH-CONH 5 CH3 k I CH3 EH N N i) o N coon 0H uCONl'1-CH-CONH E 1 Cl 11 Q o N COOH OCOOCZH5 CONHCH--CONH 5 @11 3CONHa-CH-CONHb R 0/ coon When measured in hexadeuterodimethylsuItoxideusing an instrument Varian Th0."" both the Ha and Hb in case of Y beingalkyl shift to 540-570 H2. In case of Y being alkanoyl oralkoxycarbonyl. Ha and Hh shift respectively to 630-640 Hz and 540-5 70Hz. 111 case of Y being hydrogen, Hat and H1) shift respectively to650-680 H2 and 540-570 Hz.

When determined according to the agar dilution method. the penicillins[I] afford the minimal inhihitory concentrations as shown in thefollowing Table 1 Table 1 Minimal Inhibitory Concentrations ofPenicillins 111 against Pathogenic Microorganisms (in vitrol Example MIC(pg/ml) 2091 NlHJ tin/M102 mm! 1114 I 11 11 1 4: 111 hjfi 111 lo II 7H3.11 0.25 Ht n 25 UNITED STATES PATENT ()FFICE CERTIFICATE OF CORRECTIONPatent No. 3,864,329 Dated February 4, 1975 Inventor( Hisao et a1 It iscertified that error a ppears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the heading of the patent,

[30] FOREIGN APPLICATION PRIORITY DATA:

December 29, 1970 Japan 124374/1970 December 29, 1970 Japan 124377/1970Signer and sealer? this 2 1th day of June L375.

(t5 CAI.)

Attest:

C. I-TARSHALL DAT-IN RUTI; C MASOQ Commissioner of Patents ittestlngOfficer and Trademarks please insert the following:

A DO-105D (10-69) USCOMM-DC 50376-P69 R US GOVERNMENT PRINTING nrnrr m I1 n.

1. A PENICILLIN OF THE FORMULA:
 2. D-(-)- Alpha-(7-Methyl-4-hydroxy-1,8-naphthyridine-3-carbonamido)-benzylpenicillin.3. D-(-)- Alpha-(6-Methylmercapto-4-hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.
 4. D-(-)- Alpha-(6-Dimethylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.
 5. D-(-)- Alpha-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.
 6. D-(-)-Alpha-(6-Acetylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.7. D-(-)- Alpha-(6-Methyl-4-hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.8. D-(-)- Alpha-(6-Methylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-benzylpenicillin.9. D-(-)- Alpha-(6-Dimethylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-2-thienylmethylpenicillin.
 10. D-(-)- Alpha-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)-2-thienylmethylpenicillin.11. D-(-)- Alpha-(6-Amino-4-hydroxy-1,5-naphthyridine-3-carbonamido)0-benzylpenicillin.12. D-(-)- Alpha-(4-Hydroxy-1,6-naphthyridine-3-carbonamido)-benzylpenicillin.